Novel 17-desoxy-delta1, 4-pregnadienes and preparation thereof



United States Patent 3,161,663 NQVEL 17-DESOXY-A -PREGNADIENES ANDPREPARATION TTEREQF Robert Eoiy, Mentmorency, .lulien Warnant,Neuilly-sur- Seine, dean dolly, \Clichy-sous-Eois, and Bernard Gothne't,Paris, France, assignors, by mesne assignments, to fioussel-UCLAF, S.A.,Paris, France, a corporation of rance No Drawing. Filed May 3, 1961,Ser. No. 124,248 Claims priority, application France, May 14, 1961?,827,2(55; May 16, 1968, 827,394; July 1, 1959, 831,770; July 13, 1966,832,913

10 Ciairus. ll. ass-397.45

The invention relates to novel 17-desoxy-corticosteroids having theformula:

CHzOR n' l 21:0 )3 O5 wherein R is selected from the group consisting ofhydrogen, an acyl radical of an inorganic acid and an acyl radical of anorganic carboxylic acid having 1 to 18 carbon atoms and R is selectedfrom the group consisting of OH =0 and relates to a novel process forthe compounds and novel intermediates The invention also preparation ofsaid thereof.

Cortisone activity has until now been believed to be dependent on atleast the four following structural features: the presence of a ketoneor ,B-hydroxy in the ll-position, the presence of a 17a-hydroxy group,the presence of a S-lteto group conjugated with a double bond in the4,5- position, and the presence of a lateral ketol chain oriented in the5-position either free or esterfied. This is why corticosterone or17-desoxy-hydrocortisone has a very weak anti-inflammatory andglucocorticoid activity.

Applicants have found that surprisingly the compounds of Formula I showa corticoid activity superior to that of prednisone and prednisolone inspite of the lack of a a hydroxyl in the l7-position.

l6u-methyl-h -pregnadiene-Zl-ol 3,11,20 trione and 16a-rnethyl-h-pregnadiene-l1;B,21-dio1-3,20-dione can be utilized for treatment ofall acute or chronic rheumatic addictions, of neuralgia of the nerveroots and of lumbar sciatica. They have also been found useful in thetreatment of local or generalized inflammatory reactions, in thetreatment of edemas of all natures, of infectious dermatitis, of asthmaand in the treatment of emphysema and of fibrosis.

They further have the advantage of increasing diuresis and eliminationof sodium while increasing only slightly the excretion of potassiumcontrary to cortisonic compounds used until now. Therapeutic treatmentwith the said compounds does not require, as is necessary with the usualanti-inflammatory corticosteroids, a constant intake in the organism ofpotassium salts.

It is an object of the invention to provide novel 17-desoxy-corticosteroids of Formula I.

It is another object of the invention to provide novel processes for theproduction of 17-desoXy-corticosteroids of Formula I.

It is a further object of the invention to provide novel intermediatesfor the preparation of l7-desoxy-corticosteroids.

It is an additional object of the invention to provide 3,161,663Patented Dec. 15, 1964 novel pharmaceutical compositions comprising17-desoxycorticosteroids.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

The 17 -desoxy-corticosteriods of the invention have the formula:

CHiQR L GUZ? wherein R is selected from the group consisting ofhydrogen, an acyl radical of an inorganic acid and an acyl radical of anorganic carboxylic acid having 1 to 18 carbon atoms and R is selectedfrom the group consisting of OH =0 and The acyl radical of the organiccarboxylic acid having 1 to 18 carbon atoms may be derived from analiphatic, aromatic, cycloaliphatic or heterocyclic carboxylic acid.Examples of suitable acids are alkanoic acids such as formic acid,acetic acid, propionic acid, butyric acid, isobutyric acid, valericacid, isovaleric acid, trimethyl acetic acid, caproic acid,fi-trirnethyl propionic acid, heptanoic acid, caprylic acid, pelarginicacid, capric acid, undecylic acid, lauric acid, myristic acid, palmiticacid and stearic acid; alkenoic acids such as undecylenic acid and oleicacid; cycloalkyl carboxylic acids such as cyclopentyl carboxylic acid,cyclopropyl carboxylic acid, cyclobutyl carboxylic acid and cyclohexylcarboxylic acid; cycloalkyl alkanoic acids such as cyclopentyl aceticacid, cyclohexyl acetic acid, cyclopentyl propionic acid and cyclohexylpropionic acid; arylalkanoic acids such as phenyl acetic acid and phenylpropionic acid; aryl carboxylic acids such as benzoic acid and2,4-dinitrobenzoic acid; phenoxy alkanoic acids such as phenoxy aceticacid, p-chlorophenoxy acetic acid, 2,4-dichlorophenoxy acetic acid,4-ter-butylphenoxy acetic acid, 3-phenoxy propionic acid and 4- phenoxybutyric acid; heterocyclic carboxylic acids such as furane-Z-carboxylicacid, S-ter-butylfurane-Z-carboxylic acid, S-bromofurane-2-carboxylicacid and nicotinic acids; fi-ketoalkanoic acids, such as acetylaceticacid, propionylacetic acid and butyrylacetic acid; amino acids such asdiethylarninoacetic acid and aspartic acid. Examples of other suitableacids are sulfonic acids, phosphoric acid and sulfuric acid.

The process of the invention comprises selective halogenation ofl6a-methyl-5fl'pregnane-3a-ol-11,20-dione to form the Ill-halogenatedderivative of said compound, reacting the 2l-halogenated derivative witha salt of an organic acid in an inert organic solvent to form2l-acyloxy-ISa-methyI-SB-pregnane 3a-ol-ll,20-dione, oxidizing thelatter to form 21-acyloxy-l6a-methyl-5fl-pregmane-3,11,29-trione,reacting the said trione with bromine in an orgmiic solvent to form2l-acyloxy-16a-methyl- ZeAH-dibrorno-SB-pregnane-B,11,20-trione andreacting the dibromo product with a mixture of lithium carbonatelithiumbromide in an organic solvent to form 2l-acyloxy-16a-rnethyl-A-pregnadiene-3,l1,20-trione. The latter may be subjected to methanolysisto form Mot-methyl- 17-des0xy-prednisone.

The 16a-methyl-17-desoxy-prednisone may be transformed into anyZl-acyloxy ester desired by known esterification techniques such as byreaction with an acid anhydride or with an acid halide in the presenceof a tertiary amine.

To form 16a-metl1yl-17-desoXy-prednis0lone and its esters,2l-acyloxy-16u-methyl-A -pregnadiene 3,11,20- trione is reacted with asemicarbazide salt in an organic solvent in the presence of a bufferingagent to form the 3,20-disemicarbazone of 21 acyloxy-la-methyl-Apregnadiene-3,11,20-trione, the disemicarbazone is re- FLO-- l O i C=O i]-OH l H .Br V

4 duced by action of an alkali metal borohydride such as potassium,sodium or lithium borohydride in an aqueous organic solvent to form the3,20-disemicarbazone of 16a-methyLA -pregnadiene-1 113,21-diol-3,20dione and 1he latter is hydrolyzed under acidic conditions andtransformed into the corresponding esters if desired. The reactionscheme of the process is illustrated in Table I.

TABLE I Cline-0A0 oiizoAc TABLE 1-Continued CHzOH wherein Ac is the acylradical of an organic carboxylic acid having 1 to 18 carbon atoms.

A preferred process of the invention comprises reacting16ct-methyl-55-pregnane-3u-ol-11,20-dione with bromine in a loweralkanol such as methanol in the presence of an enolizaticn agent asdisclosed in copending application Serial No. 124,247, filed May 3,1961, now abandoned, to form 2l-bromo-l6a-methyl-5fl-pregnane-3m-ol-11,20-dione, reacting the latter with an alkali metal salt of an organicacid such as sodium acetate in an inert organic solvent such asdimethylformamide to form 21- acyloxy16a-methyl-5B-pregnane-3a-ol-l1,20-dione, oxidining the said productwith chromic acid anhydride in an organic solvent such as acetone toform 21-acyloxy- 16a-methyl-55-pregnane-3,11,20-trione, brominating thelatter with bromine in an organic solvent such as ethyl acetate oracetic acid to form 2a,4;3-dibro1no-2l-acyloxy-16u-methyl-5B-pregnane-3,11,20-trione, dehydrobrominating the saidproduct with a mixture of lithium bromide and lithium carbonate in anorganic solvent such as dimethylformamide to form2l-acyloxy-lfiu-methyl-n pregnadiene-3,11,20-trione which bymethanolysis can be changed to Mot-methyl-17-desoxy-prednisone.

lGa-methyl-17-desoXy-prednisolone can be prepared by reacting2l-acyloXy-16wmethyl-n -pregnadiene-3,1 1,20- trione with semicarbazidehydrochloride in a lower alkanol such as methanol in the presence of abuifering agent such as sodium bicarbonate or disodium phosphate to formthe 3,20-disemicarbazone of 2l-acyloXy-l6wmethyl- A-pregnadiene-ll1,20-trione, reducing the latter with an alkali metalborohydride in aqueous tetrahydrofur-an to form the 3,20-disemicarbazoneof l6a-methyl-A pregnadiene-l1,6,21-diol-3,20-dione, and reacting thelatter with pyruvic acid to form 16m-methy1-17-desoxyprednisolone whichcan be esterified if desired.

Instead of selectively brominating16a-methyl-55-pregnane-3e-ol-1l,20-dione in the 21-position and thenforming 2 l-acyloxy-l 6a-methyl-5B-pregnane-3 04-01-1 1,20-dione, otherselective halogenation techniques may be used. By using the processdisclosed in copending application Serial No. 44,851, filed July 25,1960, now U.S. Patent No. 3,062,848, lGu-methyl-Sfl-Iegnane-Svt-ol-11,20-dione can be reacted with iodine in a lower alkanolsuch as methanol in the presence of calcium chloride and calcium oxideor hydroxide to form 2l-diiodo-16a-methyl-5fl-pregnane-3a-ol-l1,20-dione and the latter can be reacted with an alkali metalsalt of an organic acid in an organic solvent to form21-acyloxy-16a-methyl-55-pregnane-3a-01-11,20- dione which can befurther reacted in the process of the invention.

In the following examples there are described several preferredembodiments to illustrate the invention. How- C l O ever, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

Example I.Preparation of 16ot-Methyl-l7-Des0xy- Prednisone STEPA.-PREPARATION OF ZLBROMO-l(ia-METHYL-iifl- PREGNANT?-3a.OL-11,20-DIONETo 50 gm. of 16a-methyi-5B-pregnane-3a-ol-l1,20-dione, preparedaccording to Arth (I. Am. Chem. Soc, 80, 3160, 1958), 375 cc. ofmethanol were added and the reaction mixture heated to 30 underagitation. Then 0.4 cc. of acetyl chloride was added and 232cc. of amethanolic solution containing 12.4% of bromine were introduced over aperiod of about 20 minutes. This introduction was regulated in such afashion that there is no excess of bromine in the reaction solution. Thereaction mixture was cooled by an ice bath in such manner that thetemperature did not pass beyond 30 C. Toward the end of the introductionof the bromine solution, the solution had a yellow coloration and thespeed of absorption of the bromine diminished.

When the excess of bromine persisted for a period of 3 to 5 minutes, thereaction mixture was poured into a mixture of several liters of waterand ice, then vacuum filtered and washed with Water. After drying, 62gm. of a 3% solvate of raw 2l-bromo-l6a-methyl-5,8-pregnane3a-ol-l1,20-dione was obtained. The product tested 19.3% to 19.4% ofbromine (theoretical 18.78%); specific rotation [a] =+l17 (c.=0.5% inchloroform), and the product can be acyloxylated directly. For analysis,it was recrystallized from isopropyl ether. The product obtained had amelting point of 126 to 127 C. and a specific rotation [a] =+123.5i3(c.=0.5% in chloroform) Analysis.C H O Br; molecular weight=425 .4.Calculated: C, 62.11%; H, 7.82%; Br, 18.78%. Found: C, 6l.8%; H,7.8%;Br,18.9%.

This compound is not described in the literature.

On solution or" the said compound in formic acid and allowing it tostand for a period of 6 hours at room temperature, the 3-formate of saidcompound crystallized. it was precipitated in water, vacuum filtered,washed, dried and recrystallized from methanol and isopropyl ether. Theproduct obtained had a melting point of 168169 C. and a specificrotation [a] =+137 (c.= 0.5% in chloroform). The product was soluble inmethanol, less soluble in isopropyl ether, poorly soluble in alcohol,insoluble in water.

Analysis.C H O Br; molcular weigh*=453.4l. Calculated: C, 60.92%; H,7.33%; Br, 17.63%. Found: C, 61.1%; H, 7.5%; Br, 17.6%.

This derivative is not described in the literature.

STEP B.PREPARATION OF ZI-ACETOXY-lGwMETHYL-5B-PREGNANE-3a-OL-11,20-DIONE Into 125 cc. of dimethylformamide, therewere introduced with agitation 50 gm. of the raw compound obtained inStep A. It went into solution and, without interrupting the agitation,25 gm. of anhydrous sodium acetate and 2.5 cc. of acetic acid were addedand the reaction mixture was heated to 65 :2 for a period of 2 hours. Itwas cooled to 50 to 55 C. and 200 cc. of water were added slowly. Thereaction mixture was vacuum filtered, washed with water and dried. 44.8gm., being a yield of 95.2%, a 21-acetoxy-16m-methyl 5,6-pregnane-3at-ol-1L20-dione were obtained, which can be utilized as suchfor the following step.

For analysis the product was recrystallized from isopropyl ether andethyl acetate. The product had a melting point of 138-139 C. and aspecific rotation [a] =+96 (c.=0.5% in chloroform). It was soluble intwo volumes of boiling ethyl acetate, in benzene and chloroform,slightly soluble in ispopropyl ether and ether.

Analysis.C H -O molecular weight=404.54. Calculated: C, 71.25%; H,8.97%. Found: C, 71.4%; H,

This product is not described in the literature. I v

STEP C.PREPARATION OF 21-ACETOXY-16a-METHYL- 5-5-PREGNANE-3,11,ZO-TRIONE62 gm. of the compound obtained in Step B were dissolved under agitationin 250 cc. of acetone. Without interrupting the agitation and afterhavingvcooled the reaction mixture to C., 54 cc. of a solution of 19.3.

pregnane-3,11,20-trione was vacuum filtered, washed with water anddried. 61.7 gm. of the raw compound were obtained which were purified byrecrystallization from methylethyl ketone. There resulted by thisprocess 47 gm. (being a yield of 76% of'the pure product) of the puretriketone having a melting point of 224 C. and a specific rotation [m]|101; :2 (c.=0.5% in chloroform). The product was soluble in 10 volumesof boiling methylethyl ketone, soluble in chloroform, very soluble inacetone, very slightly soluble in alcohol, insoluble in water, ether andbenzene.

Anaylsis.C H G molecular weight=402.51 Calculated: C, 71.61%; H, 8.51%.Found: C, 71.6%; H,

This compound is not described in the literature.

STEP D.PREPARATION on 21-ACETOXY16a-METHYL-ZaAfi-DIBROMO-EiB-PREGNANE-3,11,20-TRIONE '20 gm. of the compoundobtained in the preceding step were placed in suspension in 600 cc. ofethyl acetate and the mixture was cooled to 0 C. 02cc. of concentratedhydrobromic acid was added and then slowly 5.84 cc. of bromine inproportion to its absorption was added while maintaining the temperatureat 0 C. At the start, the compound tended to dissolve in the reactionmedia, but the dibrominated derivative began to be formed and acrystallization was produced which increased in proportion to theprogress of bromination. The agitation was continued at 0 C. for onehour after the in- .troduction of bromine and then the product2l-a'cetoxy- 16oz. methyl 204,45 dibromo-Sflpregnane-Ll1,20-trione wasvacuum filtered and washed with ether until neutralized and dried. 15.7gm. of the raw compound (being of nitrogen.

with water until the wash waters were neutral.

8 a yield of 56.3%) were obtained, having a melting point (block) of 265C. and a specific rotation (c. 0.5% in dimethylforrnamide). The infraredspectra showed that the derivative was a 2a,4,8-dibrom inated compound.The product tested 27.3% or bromine (theoretical 28.5%) and wassufficiently pure for its transformation in the next step.

This compound is not described in the literature.

STEP E.PREPARATION OF 2l-ACETOXY-l6a-METHYL- A-PREGNADIENE-3,l1,20-TRIONE A mixture of 400 cc. of dimethylformamideand 40 gm. of lithium carbonate and 4-0 gm. of lithium bromide washeated to C. under agitation and under a current Then 40 gm. of thedibrominated derivative obtained in Step D were rapidly introduced andthe reaction mixture was maintained, without interrupting the agitationand the current of nitrogen, at 95 C.i2 C. for a period of 18 hours. Thereaction mixture was cooled to 60 C.. and the entire amount was pouredinto a mixture of 4 liters of Water and ice containing cc. ofaceticacid. This mixture was agitated for a period of one hour, vacuumfiltered and washed on the filter with water until the wash water wasneutral and free of bromides. After vacuum filtering and drying, 28 gm.(being a yield of 98.5%) of the raw acetate ofloot-methyll7-desoxyprednisone were obtained.

For analysis, the product was recrystallized from alcohol, then frommethylethyl ketone. The pure product had a melting point of 218 C. and aspecific rotation [ajI .=-};195:2 (c.=1% in chloroform). Ultravioletspectra: A =239 m z, e=l4,800 (alcohol). The productrwas soluble in 24volumes of boiling acetone, 30 yolumes of boiling alcohol, soluble inchloroform, very slightly soluble in ether and insoluble in water.

Analysis.-C H O molecular weight=398.48. Calculated: C, 72.33%; H,7.59%. Found: C, 72.5%;

The compound is not described in the literature.

1 gm. of the acetate prepared in Step E was placed in suspension underagitation in 15 cc. of methanol and under a current of nitrogen andasolution of 0.5 gm. of sodium bicarbonate in 7 cc. of water was added.The reaction mixture was'made to boil one hour at reflux temperature,then acidified by several drops of acetic acid and the methanol wasevaporated under vacuum. The reaction mixture was iced and 16a-methyl-A-pregnadiene-21-o1-3,11,20-trione was vacuum filtered and washed Theproduct was vacuum filtered, dried and purified'by trituration withether and recrystallization from ethyl acetate. The .pure compoundoccurred in the form of needles having a melting point of 172 C. and aspecific rotation of [a] =+200j:3 (o -0.5% in chloroform). Theultraviolet spectra'sliowed A =239240 m e=14,800 (ethanol). The productwas soluble in acetone, benzene, chloroform, very soluble in alcohol,very slightly soluble in ether, insoluble in Water.

The compound is not described in the literature.

Example II.Preparati0n of 1 6 a-M ethy l-d -Pregnadime-11B,21-Di0l-3,20-Dione (1 7-Des0xy-1 6oc-Methyl- Prednisolone) STEPA.PREPARATION OF THE 3,20-DISEMICARBA ZONE OF '2l-ACETOXY-lSa-METHYL-A-PREGNADL ENE-3,11,20-TRIONE Into 300 cc. of methanol were introduced9.7 cc. of

water and 27.2 gm. of semicarbazide hydrochloride. The

.250 cc. of t'etrahydrofuran and 250 cc. of water.

17-desoxy-lda-methylprednisone prepared by Step E of Example I wereadded and the reaction mixture was heated to reflux that was maintainedfor a period of hours. The reaction mixture was cooled to C., pouredinto a liter of a mixture of water and ice, vacuum filtered and washedwith water, vacuum filtered and dried. The raw 3,20-disemicarbazone of2l-acet'oxy-16a-methyl- A -pregnadiene-3,11,20-trione obtained weighed24 gm. (being a yield of 93%). The nitrogen content was 16.4%(theoretical 16.39%). The specific rotation [a] =+16Si1 (c.=l% indimethylformamide) (on the desolvated product). The ultraviolet spectrashowed a of 242 m (e=21,900, ethanol) and another a of 290 m (e=21,500).

The infrared spectra showed a band at 1740 cm.- indicating the presenceof an acetate function in the -2l-position.

The product is not described in the literature.

STEP B.-PREPARATION OF THE 3,20-DISEMICARBA- 3,2o-DIONE 24.15 gm. of thecompound obtained in the preceding stage were dissolved under agitationin a mixture of A solution of 5.2 gm. of potassium borohydride in amixture of 50 cc. of water and 5 cc. of normal sodium hydroxide wasadded and the reaction mixture was heated so that the interiortemperature reached C. and was maintained at this temperature for aperiod of 5 hours. A crystallization was produced in the course of thereduction. The reaction terminated. The mixture was cooled to +10 C.,acidified with acetic acid to a pH of 5 to 6 and the tetrahydrofuran wasevaporated under vacuum. A mixture of water and ice was added and themixture was vacuum filtered and Washed with water. Raw3,20-disemicarbazone of l6a-methyl-A -pregnadiene-ll5,2l-diol-3,20-dionewas obtained with a yield of 100%. It tested 17.1% of nitrogen(theoretical 17.78%) and had a specific rotation [a] =+l87i3 (c.:1% indimethylforrnamide). The ultraviolet spectra. showed;

a 240 m s=19,800 (alcohol) hmax' 290 I'm 1., s=20,000

This compound is not described in the literature.

STEP C.-PREPARATION OF 2l-ACETOXY-l6aMETHYL- APREGNADIENE-11B-OL-3.2O-DIONE (ACETATE Oill6tt-METHYLJ7DESOXYPREDNISCLONE) 22 gm. of the compound obtained in StepB were added to 44 cc. of pyruvic acid and 53 cc. of water and thereaction mixture was heated to 70 C. under agitation and under a currentof nitrogen. The mixture was maintained at this temperature for a periodof 6 hours while introducing 88 cc. of water drop by drop. Theyellow-orange suspension was poured into one liter of water and ice andwas adjusted to a pH of 9 by addition of sodium bicarbonate. The rawla-methyl-17-desoxy-prednisolone formed was vacuum filtered and washedwith water. 0n drying, 13.4 gm. of raw 1604methyl-17-desoxy-prednisolone were obtained, being a yield of 80%.

In order to transform the product into the acetate, it was dissolvedunder agitation in 100 cc. of pyridine. cc. of acetic acid anhydridewere added and the product heated for 2 hours at 40C. The solutionobtained was poured into ice water containing hydrochloric acid in orderto neutralize the pyridine and the precipitate was vacuum filtered andwashed with water. After drying, 14.2 gm. of the raw acetate of16u-methyl-17-desoxypreduisolone was obtained, which was purified bytrituration with isopropyl ether, followed by chromatography on alumina.For this, the product was taken up in a mixture of benzene and ether (90parts of benzene for 10 parts of ether), added to 50 gm. of alumina forchromatography, agitated, filtered and the alumina which rerained theresins was washed with the same mixture of solvents. The filtrates werecombined and evaporated to dryness, then taken up with ether. The saidacetate crystallized. The crystals were iced, vacuum filtered, washedwith cold ether and dried. By recrystallization from methylethyl ketone,the pure product was obtained having a melting point of 212 C. and aspecific rotation [u] =+123il (c.=0.5% in chloroform).

max. n, 5 14.900 (ethanol) The product was soluble in chloroform, fairlysoluble in alcohol, slightly soluble in benzene and acetone, veryslightly soluble in ether, insoluble in water.

Analysis.C H O molecular weight=400.5. Calculated: C, 71.97%; H, 8.05%.Found: C, 72.2%; H, 7.9.

The compound is not described in the literature.

STEP D.PREPARATION OF 16a-METHYL-A PREGN. DIENE-11B,21-DIOL-3,20-DIONE(16a-lvIETHYL-17-DES OXY-PREDNISOLONE 1.85 gm. of. the acetate preparedin Step C were agitated with 16.6 cc. of methanol in a current ofnitrogen and a solution of 0.925 gm. of sodium bicarbonate in 7.4 cc. ofwater was added. The product dissolved rapidly. After an hour of boilingat reflux under a current of nitrogen, the reaction mixture wasacidified by the addition of acetic acid until the greenish-yellowappearance of Bromothylmol Blue. The methanol was removed and thesolution was added to water and ice. TheMot-methyll7-desoxy-prednisolone formed was vacuurn filtered, washedwith water and dried. 1.5 gm. being a yield of 91%, of raw compound wereobtained. The product was purified by recrystallization from aqueousacetone. 0.9 gm. of pure 16a-methyl-l7-desoxy-prednisolone were obtainedfor analysis. The product had a melting point of 207 C. and a specificrotation[a] =+1 13- L2 (c.=0.5% in chloroform). The ultraviolet spectrashowed k =244 ma, e=15,000 (ethanol). The prodnot was very soluble inalcohol, soluble in chloroform, fairly soluble in acetone, slightlysoluble in ether, insoluble in water.

Analysis.--C H O molecular weight=358.46. Calculated: C, 73.71%; H,8.44%. Found: C, 73.5%, H, 8.4.

This compound is not described in the literature.

EXAMPLE ZII.-Preparalion of 21-A cet0xy-16u-Methyl- 5 B-Pregnane-S -Ol-11,20-Di0ne Into a mixture of 20 cc. of pure methanol and 0.5 cc. ofmethanol containing 10% calcium chloride, there were introduced undernitrogen 5 gm. of IGa-methyI-Sfipregnane-3a-ol-l1,20-dione. Then 2.5 gm.of calcium oxide were added and while maintaining the temperature at 26to 28 C. a solution of 7.32 gm. of iodine in a mixture of 10 cc. ofmethanol containing 10% calcium chloride and 5 cc. of pure methanol wereintroduced in small fractions over a period of about one-half hour. Thereaction mixture was poured into 450 cc. of water and ice containing 7.5cc. of acetic acid. The 21-diiodo-16amethyl-55-pregnane-3wold1,20-dioneformed was vacuum filtered, washed with Water and dried.

5 gm. of the diiodo derivative were introduced under nitrogen into amixture of 50 cc. of acetone, 0.5 cc. of tree tic acid and 7.5 gm. ofpotassium acetate. The reaction mixture was boiled for an hour and ahalf at reflux. Then the acetone was evaporated to concentrate thereaction mixture to a small volume and the remainder of the acetone wasremoved after the addition of water.2l-acetoxylGa-methyI-SQ-ol-pregnane-3a-11,20-dione was formed andseparated by extraction with ether. The ethereal extracts were combined,washed with water, decanted, dried over magnesium sulfate, filtered andevaporated to dryness. The residue crystallized after trituration withisopropyl ether. It was dissolved in benzene and a solvate of 21-acetoxy-16a-methyl-Sfi-pregnane-3a-ol-11,20 dione was separated byaddition of cyclohexane. This solvate was taken up with ether andallowed to stand in the refrigerator. Crystals of the desiredacetoxylated derivative having a melting point of 137-13-8 C. and aspecific rotation [a] =+96i1.5 (c.=0.5% in chloroform) formed and wereidentical to the product formed in- Step B of Example I since it give nodepression of the melting point.

The compounds of the invention may be administered by oral method, byperlingual method, by transcutaneous injections (intramuscular, intraandperiarticular injections) or by application on the skin and mucousmembranes and by rectal administration. They can be used in the form ofinjectable suspensions, contained in ampules, in multidoseflasks, in theform of implants, tablets, suppositories, pomades, creams or aqueoussuspensions.

Preferably they are used in the form of injectable suspensions containedin ampules or in multidose flasks, tablets, suppositories, pomades anddermic creams, ophthalmic pomades, collyrium and suspensions for nasalusage.

The dosage used in controlled between 5 and 30 mg. per day in the adultdepending upon the method of administration and is preferablyadministered in an amount of 5 mg. per dose.

Preparation Tablets Containing mg.

In an appropriate mixer there were introduced successively the activeprinciple, white sugar, potato starch and lactose. After homogenizingthis mixture, it was added in powdered from into an aqueous solution ofgelatin in such a concentration as was necessary and sufiicient in orderto obtain a powder capable of granulation on a perforated metallicplate.

The granules obtained were spread out in a bed on a tray and placed todry in a ventilated oven at 50 C. The dry granules were broken andpassed through a metal screen of appropriate size, then mixed with talcand magnesium stearate in order to lubricate the same. 7

The granulated powder was transformed into tablets of adequate weight bymechanical pressure in a press. The average weight tolerance of a lot often tablets is i 5% of the theoretical weight.

For ingestible commodities, it is preferable that the weight of a tabletshould not be more than 750 mg. and

should not be less than 80 mg. The percentage of active principle in thetablets is preferably between 0.6 and 6%.

A nti-lnflammatory A ctivity Tests of cotton granuloma following atechnique inspired by Singer (Proc. Soc. Exp. Biol. Med, 1956, 92, 23)were made by subcutaneous implantation of two pellets of cotton in theintact rat. 16a-methyl-A -pregnadiene-21-ol 3,11,20 trione and16u-methy1-A -pregna- 'diene 11,6,21 diol 3,20 dione were adminsteredtwo times a day orally for a period of two days. The animals weresacrificed the third day. The granuloma tissue formed was weighed.16oa-methyl-A -pregnadiene-Z1-ol- 3,11,20-trione possessed an activity40% superior to that of prednisolone and 16a-methyl-A-pregnadiene-11,6,21- diol-3,20-dione was 80 more active thanprednisolone.

The average active doses (doses which diminish by 50% the weight ofgranuloma formed) were on the order of 1.5 mg. to 2 mg./kg.

Efiects of Hydrosaline Diurcses The principle technique used wasinspired by F. Marcus (Endocrinology, 50', 286, 1952). One operated onintact male rats of 150 to 170 gm. by intraperitoneal injection of ahydrosaline solution of 5 cc. per 100 gm. of animal. The hydrosalinesolution was a solution of 9 parts per thousand of sodium chloride. Theurine was collected from 0 to 6 hours. The urinary volume was measured.Sodium and potassium were determined by flame photometry. The steroidwas injected in aqueous 12 suspension by subcutaneous methods. one hourafter the hydrosaline injection.

The values show that the increase of excretion of potassium is less thanthat of water and of sodium, contrary to that which is observed underthe same conditions with the usual cortisones.

Acute Toxicity Tests were made with mice of the Rockland strain weighingbetween 18 and 22 gm. The compounds were used at a concentration of 10mg./cc. in suspension in an aqueous dispersant. The suspensions wereinjected by subcutaneous method in doses of and 100 mg./kg. in lots of10 mice for each dosage level. The duration of observation afterinjection was one week. No sign of intoxication nor mortality was notedduring this period. Therefore, 16ot-methyl-A -pregnadiene-l1fl,21-diol-3,2O dione and 1u-methyl-A -pregnadiene-Zl-ol- 3,11,20-trione aredevoid of toxicity even at doses of 100 mg./kg. I

Various modifications of the process of the invention may be madewithout departing from the spirit or scope thereof and it is to beunderstood that the invention be limited only as defined in the appendedclaims.

Weclaim: V

1 21 -acetoxy-1 6a.-methyl-2a,4fi-dibromo-5/8-pregnane- 3,11,20-trione.

2. 3,20-disemic'arbazone of 21-acetoxy 16oz methyl A -pregnadiene-3,11,20-trione.

3. 3,20-disemicarbazone of 16a methyl-A pregna- V diene-l118,21-diol-3,2,0-dione.

4. A process for the preparation of compounds having the formula:

.3,11,20-trione, dehydrobrominating the latter to form 21-acyloxy-16u-methyl-A -pregnadiene-Zi,11,20 trione and recovering acompound of the above formula.

5. The process of claim 4 wherein the dibromo product is formed byreaction of 21-acyloxy-1Ga-methyl-Sflpregnane-3,1 1,20-trione withbromine in ethyl acetate.

6. The process of claim 4 wherein the dehydrobromination is effected inthe presence of a mixture of lithium bromide and lithium carbonate indirnethylformamide.

1 t3 7. A process for the preparation of compounds having the formula:

CHzOR wherein R is selected from the group consisting of hydrogen, anacyl radical of a mineral acid and an acyl radical of an organiccarboxylic acid having 1 to 18 carbon atoms which comprises selectivehalogenation with bromine in a lower alkanol in the presence of anenolization agent of l6a-methyl-5 3-pregnane-3a-ol-l1,20-dione in the2l-position to form 2l-halo-l6a-methyl-fifl-pregnane-3a-ol-1L2O-dione,reacting the latter with a salt of an organic carboxylic acid to form21acyl0Xy-l6amethyl-Sfi-pregnane-h ol 11,20 dione, oxidizing the productto form 2l-acyloxy-l6os-methyl SB pregnane- 3,11,20-trione, reacting thesaid trione with bromine to form2l-acyloxy-2m,4;3-dibromo-16a-rnethyl-55pregnane- 3,11,20-trione,dehydrobrominating the latter to form 21- acyloxy-la-methyl Apregnadiene 3,11,20 trione. reacting the latter with a semicarbazidesalt in an organic solvent in the presence or" a buffering agent to formthe 3,20-disernicarbazone of 21-acyloxy 16a methyl Apregnadiene-3,11,20-trione, reducing the disemicarbazone with an alkalimetal borohydride in an aqueous organic solvent to form the3,20-disemicarbazone of l6a-methyln-pregnadiene-llfi,21-diol-3,20-dione, reacting the latter under acidicconditions to form 16oc-methyl-\ -pregnadiene-l1fi,2l-diol-3,20-dioneand recovering a cornpouhd of the above formula.

8. The process of claim 7 wherein the dibrorno product is formed byreaction of 21-acyloXy-16a-rnethyl-5B- pregnane-3,ll,20-trione withbromine in ethyl acetate.

9. The process of claim 7 wherein the dehydrobroinination is effected inthe presence of a mixture of lithium bromide and lithium carbonate indimethylformamide.

10. The process of claim 7 wherein the disemicarbazide salt is asemicarbazone hydrochloride and the buffering agent is sodiumbicarbonate.

References Cited by the Examiner FOREIGN PATENTS 269,976 7/50Switzerland. 710,482. 6/ 5 4 Great Britain. 807,227 1/59 Great Britain.

OTHER REFERENCES Wendler et al.: Tetrahedron, vol. 3 (1958), pages144-159.

Arth et al.: J.A.C.S., vol. 80, June 20, 1958, page 3162.

Boland: California liedicine, vol. 88, No. 6, June, 1958.

LEVJIS GOTTS, Primary Examiner.

L. H. GASTON, M. LIEBMAN, IRVING MARCUS,

F. CAQCiAPAGL-IA, In, Examiners.

1. 21-ACETOXY-16A-METHYL-2A, 4B-DIBROMO-5B-PREGNANE3,11,20-TRIONE.
 2. 3,20-DISEMICARBAZONE OF21-ACETOXY-16A-METHYL$1,4-PREGNADIENE-3,11,20-TRIONE.